Pain, Nociception, and the Amygdal

认知障碍，如无法做出有利的决定是一个后果， 持续性疼痛，但潜在的神经机制尚不清楚（NIH PA-06 - 544）。的作用 前额叶皮层的认知功能，包括决策和避免基于情绪的风险 的选择，是很好的。前额叶皮质功能受损最近显示疼痛患者， 认知缺陷输入mPFC的主要来源是基底外侧杏仁核（BLA），这是大脑皮层的一个关键元件。 情绪-情感杏仁核回路我们之前的研究显示突触传递增强 在关节炎疼痛模型中，从BLA到杏仁核中央核（CeA）。我们假设 BLA是疼痛相关情绪-情感行为的重要基础结构（通过投射到 CeA）和认知缺陷（通过与mPFC的连接）。 为了确定BLA-mPFC相互作用在疼痛认知效应中的作用，我们将使用多学科的 结合行为，系统和细胞电生理学和药理学的方法。我们将 继续使用我们完善的疼痛模型，高岭土/角叉菜胶诱导的膝关节炎。的 本文将对以下具体假设进行检验：1.恢复BLA和mPFC的正常功能， 疼痛相关的决策缺陷2. BLA投射神经元痛敏化抑制mPFC 神经元3.疼痛导致BLA中的突触可塑性，并增加从BLA到BLA的抑制性传递。 mPFC神经元。具体目标是：1。确定是否恢复BLA中的正常功能（停用 与APS，一种NMDA受体拮抗剂）和mPFC（用荷包牡丹碱，一种GABAA 受体拮抗剂）改善疼痛相关的认知功能障碍， 人类的决策赌博任务。关节炎动物和对照动物决定在不利的 基于食物奖励的高风险和有利的低风险策略。2.关节炎的危害有哪些 BLA和mPFC神经元，并确定是否抑制BLA敏化（APS）或解除mPFC抑制 (with荷包牡丹碱）逆转体内麻醉大鼠中mPFC神经元的疼痛相关抑制。3.确定 关节炎对BLA和BLA-mPFC兴奋性和抑制性突触传递的影响 体外突触，使用关节炎和对照动物脑切片的全细胞膜片钳记录。 这个转化研究项目将确定疼痛产生的神经生物学机制。 临床记录的认知缺陷。如果我们的假设是正确的，这些研究将是第一个 证明杏仁核损害mPFC功能，导致疼痛相关的决策缺陷。的 该项目的长期目标是更好地了解不同的大脑功能， 疼痛组件，以改善疼痛管理策略和决策。

Cognitive impairment such as the inability to make advantageous decisions is one of the consequences of persistent pain but the underlying neural mechanisms are not known (NIH PA-06-544). The role of the prefrontal cortex in cognitive function, including decision-making and avoidance of emotion-based risky choices, is well established. Impaired prefrontal cortical function was recently shown in pain patients with cognitive deficits. A major source of input to the mPFC is the basolateral amygdala (BLA), a key element in the emotional-affective amygdala circuitry. Our previous studies showed enhanced synaptic transmission from the BLA to the central nucleus of the amygdala (CeA) in an arthritis pain model. We hypothesize that the BLA is an important structure underlying pain-related emotional-affective behavior (through projections to the CeA) and cognitive deficits (through connections with the mPFC). To determine the role of the BLA-mPFC interaction in cognitive effects of pain, we will use a multidisciplinary approach that combines behavior, systems and cellular electrophysiology and pharmacology.We will continue to use our well-established pain model, the kaolin/carrageenan-induced knee joint arthritis. The following specific hypotheses will be tested: 1. Restoring normal function in the BLA and mPFC improves pain-related decision-making deficits. 2. Pain-related sensitization of BLA projection neurons inhibits mPFC neurons. 3. Pain leads to synaptic plasticity in the BLA and increases inhibitory transmission from the BLA to mPFC neurons. The Specific Aims are: 1. Determine if restoring normal function in the BLA (deactivation with APS, an NMDA receptor antagonist) and in the mPFC (removing inhibition with bicuculline, a GABAA receptor antagonist) improves pain-related cognitive impairment in a novel behavioral test modeled after a decision-making gambling task in humans. Arthritic and control animals decide between disadvantageous high-risk and advantageous low-risk strategies based on food reward. 2. Analyze the effect of arthritis on BLA and mPFC neurons and determine if inhibiting BLA sensitization (with APS)or disinhibiting the mPFC (with bicuculline) reverse pain-related inhibition of mPFC neurons in anesthetized rats in vivo. 3. Determine the effect of arthritis on excitatory and inhibitory synaptic transmission in the BLA and at the BLA-mPFC synapse in vitro, using whole-cell patch-clamp recordings in brain slices from arthritic and control animals. This translational research project will determine the neurobiological mechanism by which pain produces clinically documented cognitive deficits. If our hypotheses are correct, the proposed studies will be the first to demonstrate that the amygdala impairs mPFC function resulting in pain-related decision-making deficits. The long-term goal of this project is the better understanding of higher brain functions involved in the different pain components to improve pain management strategies and decision making.